Methods and compositions for administration of oxybutynin

ABSTRACT

The present invention is directed to methods and compositions for treating pulmonary disease comprising delivering directly to a patient&#39;s lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents. Oxybutynin may be selected from the group consisting of, but not limited to, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt, a laurate salt and other salts. The pharmaceutically effective agents comprise bronchodilators, antiinflammatories, corticosteroids, corticosteroid reversal agent or alveolar growth agents or other agents selected from proteinase or protease inhibitors.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.13/728,706, filed Dec. 27, 2012, which is a CIP of U.S. application Ser.No. 12/904,964, filed Oct. 14, 2010, now U.S. Pat. No. 8,415,390, whichis a continuation in part of U.S. application Ser. No. 12/130,903, filedMay 30, 2008, now abandoned, which claims benefit to U.S. ProvisionalApplication Ser. No. 60/940,907, filed May 30, 2007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to novel methods ofadministering oxybutynin, to novel forms of oxybutynin and novel dosageforms containing oxybutynin designed for delivery via the pulmonaryroute. More specifically, the present invention comprises novel forms ofoxybutynin in combination with one or more pharmaceutically effectiveagents. The invention will be described in particular in connection withpulmonary delivery of oxybutynin for treatment of respiratory diseasessuch as asthma and chronic obstructive pulmonary disease (COPD),although other uses such as prophylactic, therapeutic or ameliorativetreatment of incontinence and intestinal hypermotility, i.e. irritablebowel syndrome, also are contemplated.

2. Description of the Prior Art

Oxybutynin is a racemic compound of the chemical formula4-diethylaminobut-2-butynyl phenylcyclohexyl-glycolate:

Oxybutynin is an anticholinergic medication that traditionally has beenused to treat urinary incontinence, urge incontinence, frequency andover-active bladder symptoms of incontinence (hereinafter singly andcollectively referred to as “urge urinary incontinence”). Oxybutyninacts by decreasing muscle spasms of the bladder. It competitivelyantagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholinereceptor. It also has weaker direct spasmolytic effects on bladdersmooth muscle as a calcium antagonist and local anesthetic, but atconcentrations far above those used clinically. It is available orallyin generic formulation and as the chloride salt, and as the brand-namesDITROPAN® and DITROPAN XL®, and as a transdermal product as a patchunder the brand-name OXYTROL® or as a gel under the brand nameGELNIQUE™.

Oxybutynin currently is administered in oral formulation as a tablet ormultiple tablets and a syrup, or transdermally as a patch or topical gelfor treating urge urinary incontinence. However, oral delivery of atherapeutically active amount of oxybutynin suffers from a number ofdisadvantages:

(1) Oxybutynin administered in an oral formulation is absorbed from theintestinal track at an undesirably slow and uneven rate with a variablemetabolism that leads to undesirable variations in blood levels andundesirably high dosage rates to achieve a therapeutic response leadingto undesirable side effects;

(2) Oxybutynin administered in an oral formulation does not producedesirably high blood levels in a desirably short period of time;

(3) Oxybutynin administered in an oral formation may result in asignificant amount not reaching targeted tissues because it is beingwasted by metabolism or excretion;

(4) Oxybutynin administered in an oral formation is contraindicated forpatients with gastrointestinal obstruction disorders because of the riskof urinary retention; and

(5) Oxybutynin administered in oral formulation requires chronic dosingwith significant and severe side effects, including dry mouth(xerostomia), constipation, mydriasis, blurred vision, drowsiness,nausea, palpitations, tachycardia and dizziness.

(6) Oxybutynin administered in the oral formulation is subject to firstpass metabolism, resulting in the formation of metaboliteN-desethyloxybutynin (DEO) which has been attributed to cause themajority of the aforementioned side effects.

As a result, many patients discontinue oral anticholinergic therapy.These adverse effects have been associated with relatively high levelsof oxybutynin's primary metabolite, DEO, which circulates inconcentrations approximately 4 (oxybutynin ER) to 10 (oxybutynin IR)times that of the parent compound. DEO has been shown to have a greateraffinity and binding duration at receptors in the salivary glands thandoes oxybutynin. In other words, the metabolite DEO has shown to have ahigher side effect-to-efficacy ratio than the parent compoundoxybutynin. Levels of DEO in oral and transdermal therapy have beenreported to be approximately 10-40 ng/mL and 3 ng/mL, respectively. Tocompletely eliminate the side effect concerns of this drug, it would beadvantageous to decrease the DEO levels in systemic circulation to belowthose found in current therapies (i.e. below 3 ng/mL).

Moreover, there are other disadvantages to current oral administrationof oxybutynin, including:

(7) Oxybutynin administered in an oral formation is administered as atablet or multiple tablets which may lack the desirable ease ofadministration because some people may dislike the swallowing oftablets, or may have difficulty swallowing tablets, or are unable toswallow tablets, or may require a liquid to assist swallowing oftablets; and

(8) Oxybutynin-containing tablets also contain several inactiveingredients, including significant amounts of lactose, corn starch,magnesium silicate, magnesium stearate, and talc which may be consideredundesirable because some people may dislike or be allergic to one ormore of these inactive ingredients that comprise the oxybutynin tablets.

Transdermal delivery of oxybutynin has many of the aforesaiddisadvantages. Additionally, some patients suffer skin irritation fromtransdermal patches, have difficulty maintaining and toleratingpatch-to-skin contact, or dislike the aesthetics of a transdermal patch.

Bronchoconstriction, a hallmark of pulmonary disease such chronicobstructive pulmonary disease and asthma, involves the narrowing of airpassages (bronchi and bronchioles) in the lungs due to musclecontraction. Often times the muscle contraction is a result ofactivation of muscarinic receptors on the membranes of smooth musclecells. This results in the limitation of air flowing to and from thelung and causes shortness of breath and overall difficulty in breathing.

Pulmonary disease includes, but is not limited to, acute bronchitis,acute respiratory distress syndrome (ARDS), asbestosis, asthma,atelectasis, aspergilliosis, bronchiectasis, bronchiolitis,bronchopulmonary dysplasia, byssinosis, chronic bronchitis,coccidiomycosis, chronic obstructive pulmonary disease (COPD), cysticfibrosis, emphysema, eosinophilic pneumonia, hantavirus pulmonarysyndrome, histoplasmosis, human metapneumovirus, hypersensitivitypneumonitis, influenza, lung cancer, lymphangiomatosis, mesothelioma,necrotizing pneumonia, nontuberculosis Mycobacterium, pertussis, pleuraleffusion, pneumoconiosis, pneumonia, primary ciliary dyskinesia, primarypulmonary hypertension, pulmonary arterial hypertension, pulmonaryfibrosis, pulmonary vascular disease, respiratory syncytial virus,sarcoidosis, severe acute respiratory syndrome, silicosis, sleep apnea,sudden infant death syndrome, and tuberculosis. The most common lungdiseases generally comprise asthma, bronchitis, COPD, emphysema, andpneumonia.

Of all pulmonary diseases, the most prevalent appears to be COPD.According to the World Health Organization estimates in the year 2004,64 million people had COPD and 3 million people died of COPD. WHOpredicts that COPD will become the third leading cause of deathworldwide by 2030. The Merck Manual (2011) provides that an estimated 12million people in the US have COPD and describes COPD as the 4th leadingcause of death, resulting in 122,000 deaths in 2003 compared with 52,193deaths in 1980. From 1980 to 2000, the COPD mortality rate increased 64%(from 40.7 to 66.9/100,000). Prevalence, incidence, and mortality ratesincrease with age and though prevalence is higher in men, totalmortality is similar in both sexes. Incidence and mortality aregenerally higher in caucasians, blue-collar workers, and people withfewer years of formal education, probably because these groups have ahigher prevalence of smoking. COPD is increasing worldwide because ofthe increase in smoking in developing countries, the reduction inmortality due to infectious diseases, and the widespread use of biomassfuels.

Current therapeutic agents for COPD predominately comprisebronchodilators administered via inhalation, including inhaledlong-acting beta₂-agonists (LABA) or long acting muscarinic antagonists(LAMA). Although oxybutynin is a LAMA, no effective pharmaceutical form,or method of administration has heretofore been developed to treat COPDusing oxybutynin. Many diseases of the respiratory tract are known torespond to treatment by the direct application of therapeutic agents. Asthese agents are most readily available in dry powdered form, theirapplication is most conveniently accomplished by inhaling the powderedmaterial through the nose or mouth. This powdered form can result in thebetter utilization of the medicament in that the drug is depositedexactly at the site desired and where its action may be required; hence,very minute doses of the drug are often equally as efficacious as largerdoses administered by other means, with a consequent marked reduction inthe incidence of undesired side effects and medicament cost. Inaddition, a drug in dry powder form may be used for treatment ofdiseases other than those of the respiratory or pulmonary system. Whenthe drug is deposited on the very large surface areas of the lungs, itmay be very rapidly absorbed into the blood stream; hence, this methodof application may take the place of administration by injection,tablet, or other conventional means.

Although some forms of oxybutynin hydrochloride compositions have beencontemplated for administration in dry powder form, no such forms haveyet been successfully reduced to practice. There remains a need foroxybutynin therapeutic compositions that are clinically effective andhaving the appropriate physiochemical properties.

Thus, there is a need for improved delivery of oxybutynin, which willprovide enhanced bioavailability, minimized variations in blood levels,and achieve more rapid onset of activity, as compared to oral dosage ortransdermal dosage forms, while at the same time providing relative easeof administration and reduced side effects compared to current oral andtransdermal delivery methods for administering oxybutynin.

SUMMARY OF THE INVENTION

The foregoing and other objects of the invention are achieved byproviding methods and compositions for pulmonary delivery of oxybutyninto a mammalian host, particularly a human patient, whereby to providefor rapid absorption of oxybutynin while avoiding the above and otherdisadvantages of oral and transdermal administration. More specifically,the present invention relates to novel dosage foams and compositions ofoxybutynin for treating pulmonary and respiratory diseases, includingbut not limited to, chronic obstructive pulmonary disease and asthma. Incertain embodiments, the present invention is also related to improvingunderlying physiological dysfunction contributing to pulmonary disease.The present invention provides effective administration of therapeuticagents to specific airways of the lungs by utilizing controlled sitedelivery.

More particularly, it has been discovered herein thatoxybutynin-containing compositions can be usefully administered tomammals by pulmonary delivery at lower dosage levels to elicit atherapeutic response with a marked reduction in systemic metabolites. Itis understood that the major contributor to the untoward effects ofoxybutynin therapy is systemic levels of the metabolite, DEO. Anincreased contribution of DEO toward side effects is due to its greateraffinity toward receptors in non-targeted tissues, i.e. salivary glands.In addition, this invention can provide enhanced bioavailability,achieve more rapid onset of activity, and ease of administration, ascompared to conventional oral and transdermal methods of administration,for treating urinary incontinence. Pulmonary delivery of oxybutyninprovides relief for treating respiratory diseases such as chronicobstructive pulmonary disease (COPD) and asthma, as well as relief fortreating both urinary incontinence and for treating stress urinaryincontinence, as well as intestinal hypermotility, i.e. irritable bowelsyndrome. The present invention also provides novel forms of oxybutyninas well as novel dosage forms and treatment protocols for administeringoxybutynin.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present invention will be seenfrom the following detailed description, taken in conjunction withaccompanying drawings, in which:

FIG. 1 plots inhibition of methacholine induced bronchoconstriction ofoxybutynin and oxybutynin salts at 18 hours. More particularly, changesin bronchoconstriction for oxybutynin treated animals were compared thetime matched lactose control animals using ANOVA followed by Dunnettstest. ** P<0.01.

FIG. 2 compares inhibition of methacholine induced bronchoconstrictionby oxybutynin, oxybutynin salts, tiotropium and glycopyrrolate at 18hours and 24 hours. More particularly, FIG. 2 plots a comparison of thebronchoconstriction evoked by methacholine (MCh, 10 μg/kg, i.v.) 18, and24 h after lactose (2 mg, i.t., n=6), oxybutynin base (2 mg, i.t., n=6),oxybutynin HCl (2.5 mg, i.t., n=6), oxybutynin xinafoate (3 mg, i.t.,n=6), tiotropium (1 mg/kg, i.t., n=6) or glycopyrrolate (1 mg/kg, i.t.,n=6) administration. Each bar represents the mean value and the verticallines show s.e. mean. Changes in bronchoconstriction for oxybutynin ortiotropium treated animals (anaesthetized guinea pigs) were compared thetime matched lactose control animals using ANOVA followed by Dunnettstest. ** P<0.01.

FIG. 3 is a series of graphs comparing changes from control responseevoked by methacholine over time by oxybutynin xinafoate and tiotropiumin pulmonary inflation pressure, mean arterial blood pressure and heartrate. More particularly, FIG. 3 plots a comparison of the changes fromthe control response evoked by methacholine (10 μg/kg⁻¹, i.v.) over time(h) in the presence of lactose (i.t., n=6), oxybutynin xinafoate (7.5%w/w, i.t., n=6), or tiotropium (1 mg, i.t., n=6) in pulmonary inflationpressure (PIP), mean arterial blood pressure (MAP) and heart rate (HR).Each point represents the mean value and the vertical bars show s.e.mean. Percentage changes in oxybutynin or tiotropium treated animalswere compared to the respective lactose control animals (anaesthetizedguinea pigs) using ANOVA followed by Dunnetts test. * P<0.05, ** P<0.01.

FIG. 4 shows pharmacokinetics of pulmonary administration of oxybutyninover time. More particularly, FIG. 4 plots anaesthetized guinea pig(n=5) pharmacokinetic profile of Oxybutynin, Oxybutynin enatiomers, andmajor metabolite (desethyloxybutynin) following dry powder insufflation.

FIGS. 5 and 6 provide 1H NMR and FT-IR structure analysis.

FIG. 7 provides HPLC analysis.

FIGS. 8 and 9 provide crystallinity, compound purity, and melting pointdetermined by XRPD and DSC.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention may be understood more readily by reference to thefollowing detailed description of the specific embodiments includedherein. Reference is made to the accompanying drawings, which form apart hereof, and in which is shown, by way of illustration, variousembodiments of the present disclosure. Although the present inventionhas been described with reference to specific details of certainembodiments thereof, it is not intended that such details should beregarded as limitations upon the scope of the invention. The entire textof the references mentioned herein are hereby incorporated in theirentireties by reference including U.S. patent application Ser. No.12/904,964 filed Oct. 14, 2010, and U.S. application Ser. No.12/130,903, filed May 30, 2008. Also incorporated by reference is U.S.patent application Ser. No. 13/246,686 filed Sep. 27, 2011.

Pulmonary delivery of oxybutynin to the respiratory tract can be usedadvantageously to treat respiratory disease, urge urinary incontinenceand symptoms of stress urinary incontinence. Unlike conventional oraland transdermal delivery of oxybutynin which require chronic dosing withsignificant side effects and require hours to reach therapeuticallyactive blood levels, dry powder pulmonary delivery of oxybutynin permitsa patient to enjoy relief at significantly lower doses with concomitantreduction in side effects such as dry mouth. Dry powder pulmonarydelivery of oxybutynin also permits a patient to enjoy relief fromsymptoms of stress urinary incontinence on a more immediate or as-neededbasis. Similarly, dry powder pulmonary delivery of oxybutynin permits apatient to achieve prophylactic relief from symptoms of respiratorydistress or on an as needed basis.

A feature and advantage of the present invention that results frompulmonary delivery of oxybutynin is that the typical primary metaboliteformation of DEO is largely avoided as are the adverse side effectsresulting therefrom as above mentioned.

Additionally, we have found that certain salts of oxybutynin, whenadministered via pulmonary delivery result in a significantly longeracting efficacy effect than anticipated given that the oral half life isonly 2.5 hours. These salts include a novel salt form of oxybutynin,namely the xinafoate salt of oxybutynin which heretofore has not beenreported in the literature. For example, all dosing of oxybutynin istypically three times daily due to a relatively short half-life of 2.5hours with minimal plateau levels of drug remaining at approximatelyeight (8) hours. On the other hand, pulmonary delivery of a salt ofoxybutynin unexpectedly provides a duration of activity in guinea piglungs of up to 18 hours which would translate into one to twice dailyhuman dosing. This is illustrated in FIG. 1 attached.

The xinafoate salt of oxybutynin is prepared by reacting oxybutynin withxinafoic acid in methyl tent-butyl ether under an inert (nitrogen)atmosphere. Other salts of oxybutynin that advantageously can beadministered by pulmonary delivery include palmitate, pamoic, resinate,laurate and stearate salts and also esters of oxybutnin, and can provideunexpected results of improved half-life as well as reduced adversemetabolite production.

In selecting a preferred configuration of oxybutynin for therapeuticadministration, the inventors herein contemplated several properties ofvarious oxybutynin salts, including but not limited to the following:

-   -   Solubility→PK, bioavailability, and changes in dissolution rate.    -   Surface energy→aerosolization (dispersibility), physical        stability (of particles)    -   Hydration state→stability, solubility    -   Kinetics of degradation→stability    -   Crystal hardness→micronization, physical stability    -   Hygroscopicity→handling, stability    -   Dissolution    -   Melting point    -   Dosage form to be developed    -   Route of administration    -   Loading in dosage form    -   Toxicology of counterions, especially pulmonary toxicology

As a free base, oxybutynin is poorly soluble and lipophilic, having anaqueous solubility and Log P of 0.01 mg/mL and 3.3, respectively. Toimprove drug solubility, oral oxybutynin was formulated as ahydrochloride salt, improving the gastric solubility to 20 mg/mL(measured at pH 4) (see U.S. Pat. No. 6,087,396). For the purposes ofpulmonary delivery, the inventors herein developed an alternate strategywhere a less soluble, more lipophilic salt form was engineered. It hasbeen noted previously that a slow dissolution rate and potential forlipophilic binding in vivo may prolong drug retention in the lung anddelay absorption into systemic circulation. The corticosteroidstriamcinolone acetonide and fluticasone propionate have shown meanabsorption times in the lungs of 2.9 hours and 5-7 hours, respectively(Patton (2007) Nature Reviews in Drug Discovers, V6, p67-74). Toincrease the potential for lung retention, the xinafoic acid (xinofoate)salt of oxybutynin was synthesized. Other lipophilic salts, such asstearates and palmitates were attempted; however, it was experimentallydetermined that the thermodynamic driving force indicated by thedifference in pKa of oxybutynin and xinafoic acid (8.24 vs. 2.7) wouldmore likely result in salt formation.

Before conducting salt synthesis studies, the solubility of oxybutyninin various organic solvents was evaluated (Table 1). These solubilitystudies indicated a number of potential solvents to use during saltsynthesis; however, only methyl tert-butyl ether (MTBE) producedcrystalline salt and acceptable yields. The synthesis andcrystallization methods were adapted from a method used to synthesizeoxybutynin hydrochloride (U.S. Pat. No. 6,140,529). In the patentedmethod, ethanol is added to MTBE to precipitate salt crystals; however,since the xinafoate salt is likely much less soluble than thehydrochloride, water was used to induce precipitation of oxybutyninxinafoate. The results and specifications of all salt synthesisexperiments are summarized in Table 2. Example 3 provides a descriptionof the process used for synthesizing oxybutynin xinafoate salt.

TABLE 1 Oxybutynin Solubility in Various Organic Solvents SolventOxybutynin Solvent Temp Solvent Class Wt (mg) Volumes (° C.) Result THFII 20.4 5 23 Soluble Methyl lI 18.4 5 23 Soluble THF i-PrOAc III 20.7 523 Soluble EtOAc III 19.5 5 23 Soluble MTBE III 21.7 5 30 Soluble; Norecrystallization Toluene II 22.0 5 23 Soluble Ethanol II 21.9 5 31Soluble; No recrystallization 2- III 20.8 5 39 Soluble; Propanol Norecrystallization Acetone III 20.8 5 23 Soluble Methanol II 18.1 5 23Soluble

TABLE 2 Salt Synthesis Experiments Entry Acid Solvent Solvent Temp %(scale) (equiv) (1) (vol) (2) (vol) (° C.) Isolation Recovery Comments 1Xinafoic MTBE EtOH 45 Evaporation 94 Foam; (0.5 g) (1) (3 vol) (4) 1:1salt by NMR; 1.2% residual EtOH 2 Xinafoic MTBE MTBE 50 Cooled to 92Foam; (0.5 g) (1) (3 vol)   (5.4) 5° C.; then 1:1 salt by NMR;evaporated 3% residual MTBE 3 Xinafoic 2-PrOAc none 50 Cooled to 101Oil; (0.5 g) (1) (6 vol) 5° C.; then 1:1 salt by NMR; evaporated 5.5%residual IPAc 4 Xinafoic 2-PrOH none 80 Evaporated 86 Oil; (0.5 g) (1)(10 vol)  1:1 salt by NMR 5 Xinafoic Methyl THF none 80 Evaporated 106Oil; (0.5 g) (1) (10 vol)  1:1 salt NMR 6 Xinafoic Toluene none 80Evaporated 112 Oil; (0.5 g) (1) (10 vol)  1:1 salt NMR 7 Xinafoic MIBKnone 80 Evaporated 118 Oil; (0.5 g) (1) (10 vol)  1:1 salt NMR 8Xinafoic Water 2-PrOH 80 Evaporated 99 Oil; (0.5 g) (1) (10 vol)  (10) 1:1 salt NMR 9 Xinafoic MTBE EtOH 50 Crystallized 77 1:1 salt;   (3 g)(1) (3 vol) (4) 0.16% residrual MTBE Crystalline by XRPD; DSC: 104-106°C. 10  Xinafoic MTBE none 50 Crystallized 89 1:1 salt;   (3 g) (1) (5vol) 0.23% residrual MTBE; Crystalline by XRPD; DSC: 104-106° C. 11 Xinafoic MTBE none 50 Crystallized 89 1:1 salt by NMR;  (20 g) (1) (5vol) 0.27% residual MTBE; 0.057% residual H₂O (KF)

Preferred embodiments of the present invention comprise methods andcompositions for treating pulmonary disease comprising deliveringdirectly to a patient's lungs a therapeutically effective amount ofoxybutynin in combination with one or more pharmaceutically effectiveagents. In certain embodiments, the oxybutynin and the pharmaceuticallyeffective agent(s) are delivered in dry powder form. The dry powderoxybutynin may be selected from the group consisting of, but not limitedto, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt,a laurate salt and other salts. Pharmaceutically effective agentscomprise bronchodilators, antiinflammatories, corticosteroids,corticosteroid reversal (CR) agents, alveolar growth agents or otheragents selected from proteinase or protease inhibitors.

In certain preferred embodiments, the bronchodilators compriselong-acting and short-acting beta agonists and derivatives orpharmaceutically acceptable salts thereof. The anti-inflammatories mayinclude inhaled corticosteroids, phosphodiesterase inhibitors orleukotriene receptor antagonists. Furthermore, the corticosteroids maycomprise budesonide, fluticasone, beclomethasone, flunisolide,mometasone, triamcinolone, ciclesonide, loteprednol, fluorometholone,and derivatives or pharmaceutically acceptable salts thereof.

Alternative embodiments may optionally comprise corticosteroid reversalagent comprising vitamin D, synthetic vitamin D, vitamin D analogs,vitamin D receptor agonists, vitamin D receptor partial agonists,calcitriol, antioxidants, iNOS inhibitors,Phosphoinositide-3-kinase-.delta. inhibitors, p38 MAP kinase inhibitors,JNK inhibitors, MIF inhibitors, low-dose theophylline, p-glycoproteininhibitors, macrolides, calcineurin inhibitors, statins, and equivalentsthereof. In addition, the alveolar growth agents may comprise vitamin A,All Trans Retinoic Acid (ATRA), retinoic acid receptor (RAR) agonistsand RAR selective alveolar growth agents, RAR selective agonists,palovarotene and equivalents thereof.

In preferred embodiments, the present invention comprises methods andcompositions for treating pulmonary disease comprising deliveringdirectly to a patient's lungs a therapeutically effective amount ofoxybutynin in combination with a LABA wherein the oxybutynin is presentin the form of oxybutynin xinofoate and the LABA is selected from thegroup including, but not limited to, formoterol, salmeterol, odalaterol,carmoterol, vilanterol.

In alternatively preferred embodiments, the present invention comprisesmethods and compositions for treating pulmonary disease comprisingdelivering directly to a patient's lungs a therapeutically effectiveamount of oxybutynin in combination with a LABA wherein the oxybutyninis present in the form of oxybutynin xinofoate and the LABA is selectedfrom the group including, but not limited to, formoterol, salmeterol,odalaterol, carmoterol, vilanterol and further comprising an inhaledcorticosteroid (ICS) wherein the ICS comprises budesonide, fluticasone,mometasone, or additionally, a selective agent selected from the ‘softsteroid’ class, for instance, ciclesonide or loteprednol.

In alternatively preferred embodiments, the present invention comprisesmethods and compositions for treating pulmonary disease comprisingdelivering directly to a patient's lungs a therapeutically effectiveamount of oxybutynin in combination with a LABA, and further comprisinga CR reversal agent wherein the oxybutynin is present in the form ofoxybutynin xinofoate, the LABA is selected from the group including, butnot limited to, formoterol, salmeterol, odalaterol, carmoterol,vilanterol and the CR reversal agent is selected from the groupincluding, but not limited to, vitamin D, vitamin D analogs, syntheticvitamin D, vitamin D receptor agonists and antagonists, calcitol andequivalents thereof.

In alternatively preferred embodiments, the present invention comprisesmethods and compositions for treating pulmonary disease comprisingdelivering directly to a patient's lungs a therapeutically effectiveamount of oxybutynin in combination with a LABA, a CR reversal agent,and further comprising an ICS, wherein the oxybutynin is present in theform of oxybutynin xinofoate; the LABA is selected from the groupincluding, but not limited to, formoterol, salmeterol, odalaterol,carmoterol, vilanterol; the CR reversal agent is selected from the groupincluding, but not limited to, vitamin D, vitamin D analogs, syntheticvitamin D, vitamin D receptor agonists and antagonists, calcitol andequivalents thereof; and the ICS is selected from the group including,but not limited to, budesonide, fluticasone, mometasone, oradditionally, a selective agent selected from the ‘soft steroid’ class.

In alternatively preferred embodiments, the present invention comprisesmethods and compositions for treating pulmonary disease comprisingdelivering directly to a patient's lungs a therapeutically effectiveamount of oxybutynin in combination with a LABA, an alveolar growthagent, wherein the LABA comprises formoterol and the alveolar growthagent is selected from the group including, but not limited to, ATRA,cis-retionoic acid and palovarotene.

The above embodiments may be delivered using a dry powder inhaler (DPI),a DPI comprising a piezo vibrator, metered dose inhaler (MDI) or liquidnebulizer. In addition, the therapeutic compositions of theabove-described embodiments may be delivered in dry powder form having amass median aerodynamic particle size selected from the group consistingof 0.5-20 microns, 0.5-15 microns, 0.5-10 microns, or 0.5-5 microns. Thedosages of the therapeutically effective amount of oxybutynin incombination with one or more pharmaceutically effective agents is withinthe range of 0.001 to 20 mg per day, 0.02 to 15 mg per day, or 0.05 to10 mg per day administered as needed.

Terms and Definitions

As used herein, the term “oxybutynin” is intended to encompass not onlyoxybutynin as an anhydrous powder, but any salt or derivative ofoxybutynin having antispasmodic, anticholinergic activity likeoxybutynin, and which is non-toxic and pharmacologically acceptable, forexample, oxybutynin xinafoate or oxybutynin hydrochloride. Othersuitable salts include but are not limited to the palmitate, pamoic,resonate and laurate salts.

“An effective amount,” as used herein, is an amount of thepharmaceutical composition that is effective for treating pulmonarydisease, urinary incontinence or irritable bowel syndrome i.e., anamount of oxybutynin of a defined aerodynamic particle size suitable forabsorption in the lungs, that is able to reduce or eliminate thesymptoms of COPD, asthma, urinary and stress incontinence.

“A pharmaceutical composition,” as used herein, means a medicament foruse in treating a mammal that comprises oxybutynin in a dry powder formof a defined aerodynamic particle size prepared in a manner that issuitable for pulmonary administration to a mammal. A pharmaceuticalcomposition according to the invention may also, but does not ofnecessity, include a non-toxic pharmaceutically acceptable carrier.

“A defined aerodynamic particle size,” as used herein, means particleshaving a size sufficiently small so as to be delivered to the lungs. Foroptimal delivery to the lungs, the dry powder form of the oxybutyninpreferably should be micronized or spray dried to a mass medianaerodynamic diameter powder size of 0.05-20 microns, 0.5-15 microns,0.5-10 microns, or 0.5-5 microns. However, other methods for producingcontrolled size particles, e.g. supercritical fluid processes,controlled precipitation, etc., also advantageously may be employed.

“A therapeutically effective amount” as used herein will vary with theage, weight and general physical condition of the individual, frequencyof dosing, severity of COPD, asthma, incontinence, and whether urge orstress incontinence, or irritable bowel syndrome is being treated.Generally for treating respiratory diseases, a therapeutically effectiveamount will comprise the active ingredient in a quantity of from 0.001to 20 mg per day, 0.02 to 15 mg per day, or 0.05 to 10 mg per day,administered as needed. Generally, for treating urge incontinence, atherapeutically effective amount will comprise the active ingredient ina quantity of from 1 to 20 mg/day, preferably 1 to 10 mg/day. The activeingredient may be given once a day. Preferably, however, the activeingredient will be administered in smaller doses two or three or moretimes a day to maintain more consistent plasma levels. When used fortreating stress incontinence, or irritable bowel syndrome, atherapeutically amount will comprise the active ingredient in a quantityof from 0.1 to 15 mg per day, preferably 0.2 to 10 mg/day, generallyadministered as a single dose, or as needed. The active ingredient maybe given once a day. Preferably, however, the active ingredient will beadministered in smaller doses two or three or more times a day tomaintain more consistent plasma levels.

The oxybutynin may be delivered in dry powder form, e.g. via a drypowder inhaler (DPI), metered dose inhaler (MDI), or dissolved in asuitable liquid for nebulization in a therapeutically effective unitdose delivery amount. For treating acute symptoms of respiratorydistress, a dose of oxybutynin should be taken at the first sign ofrespiratory distress. For treatment of chronic respiratory distress,oxybutynin should be taken daily according to a regimen recommended by aphysician. Similarly, treating symptoms of stress urinary incontinence,a dose of oxybutynin should be taken at the first sign of stress, orupon onset of the first sign of urgency or just prior to anticipatedonset of stress, e.g. just before a patient is scheduled to talk infront of an audience. In a preferred embodiment of the invention, thedry powder oxybutynin is packaged for delivery in a piezo-electronic drypowder inhaler such as described in U.S. Pat. No. 6,026,809. The terms“fine drug particles,” and “aerodynamic particle size” as used herein,mean particles having a size sufficiently small so as to be delivered tothe airways of the lungs, and especially to the small airways. Foroptimal delivery to the lungs, the dry powder form of the therapeuticagents described herein preferably should be micronized, spray dried, orengineered to a maximum aerodynamic particle size in the range of 0.01μm to 20 μm, from 0.25 μm to 5 μm, or from 0.5 μm to 4 μm.

As used herein, the term “agent for reversal of CR” is intended toencompass any agent that when administered at an effective level willincrease the anti-inflammatory response induced by a corticosteroid.This term applies not only agents for reversal of CR, but any salt orderivative of said agent having activity to reverse CR, and which isnon-toxic and pharmacologically acceptable.

As used herein, CR reversal agents, include but are not limited to,vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptoragonists and antagonists, calcitol, theophylline and equivalentsthereof. Also included are CR reversal agents known to those skilled inthe art.

As used herein, the term “vitamin D” is intended to encompass vitamin D,vitamin D2, vitamin D3, vitamin D analogs, synthetic vitamin D, vitaminD receptor agonists and antagonists, calcitriol, calcitol andequivalents thereof.

As used herein, the term “vitamin A” is intended to encompass thoseagents that interact with Retinoic Acid Receptor (RAR) including but notlimited ATRA, ATRA derivatives, RAR agonists, 13-cis Retinoic acid andRAR selective agonists for example, palovarotene.

As used herein, the term “alveolar growth agent’ is intended toencompass any agent that promotes the growth of new alveoli via theretinoic acid receptor, and includes ATRA or RAR selective agenttherapy.

As used herein, the term “alveolar maintenance agent” is intended toencompass any agent that when administered at an effective level willincrease the anti-inflammatory response induced by COPD, COPDe andemphysema and any undesirable effects of ATRA or RAR selective agenttherapy. This term applies not only to agents for alveolar maintenance,but any salt, hydrate, prodrug or derivative of said agent havingsimilar activity, and which is non-toxic and pharmacologicallyacceptable.

As used herein, bronchodilating substances include, but are not limitedto, beta2-agonists (short and long acting, LABA), long acting muscarinicantagonists (LAMA), anticholinergics (short acting), and theophylline(long acting). “Co-administered,” as used herein, means to deliver morethan one pharmaceutical or therapeutic agent, for example, bothcorticosteroid and agent for reversal of CR as an aerosol within thesame breath via the pulmonary route.

“An effective amount,” as used herein, is an amount of thepharmaceutical composition that is effective for achieving a desiredtherapeutic effect, including but not limited to bronchodilation, CRreversal, anti-inflammation, alveolar regrowth. For example, aneffective amount of an agent for reversal of CR may comprise thespecified amount of calcitriol, within a defined aerodynamic particlesize range suitable for absorption in the lungs, that is able to reduceor eliminate the resistance to corticosteroids.

As used herein, “pharmaceutical” and “therapeutic” agents include butare not limited to any and all medicaments and pharmaceutical agents andformulations that may be administered for the treatment of pulmonarydisease, including agents for preventing disease and including agentsfor maintaining improvement of disease condition. As used herein, suchtherapeutic and pharmaceutical agents include, but are not limited to,corticosteroids, muscarinic antagonists, macrolides, and non-steroidalanti-inflammatory drugs (NSAIDs), antioxidants, iNOS inhibitors,phosphoinositide-3-kinase-δ inhibitors, p38 MAP kinase inhibitors, JNKinhibitors, MIF inhibitors, p-glycoprotein inhibitors, macrolides,calcineurin inhibitors, and vitamin D, synthetic vitamin D, vitamin Danalogs, calcitiol, vitamin A, All Trans Retinoic Acid (ATRA), retinoicacid receptor (RAR) agonists, RAR selective alveolar growth agents,budesonide, fluticasone, beclomethasone, flunisolide, triamcinolone,mometasone, ciclesonide, loteprednol, fluorometholone as well as anyderivative, equivalent or pharmaceutically acceptable salt thereof.

A “pharmaceutical” or “therapeutic” composition as used herein, means amedicament for use in treating a patient, for example, an agent forreversal of CR in a dry powder form of a defined aerodynamic particlesize prepared in a manner that is suitable for pulmonary administrationto a patient. A pharmaceutical composition according to the inventionmay optionally, include a non-toxic pharmaceutically acceptable carrier.In certain embodiments “pharmaceutical” or “therapeutic” composition maycomprise a singular entity (i.e. calcitriol alone), or a combination ofcompositions selected from the group consisting of CR reversal agents,anti-inflammatory agents, bronchodilators, alveolar growth agents, andothers.

It should be emphasized that the above-described embodiments of thepresent device and process, particularly, and “preferred” embodiments,are merely possible examples of implementations and merely set forth fora clear understanding of the principles of the disclosure. All these andother such modifications and variations are intended to be includedherein within the scope of this disclosure and protected by thefollowing claims. Therefore the scope of the disclosure is not intendedto be limited except as indicated in the appended claims.

The following specific examples will illustrate the invention as itapplies to the methods of treatment using the inhaler. It will beappreciated that other examples, including minor variations inprocedures will be apparent to those skilled in the art, and that theinvention is not limited to these specific illustrated examples.

EXAMPLES Example 1 Micronization of Oxybutynin

Oxybutynin in crystalline form is micronized to a median aerodynamicparticle size of less than 10 microns. The powder is packaged in a drypowder inhaler (DPI) made in accordance with U.S. Pat. No. 6,026,809.

Example 2 Micronization of Oxybutynin Chloride

Example 1 was repeated, using micronized oxybutynin chloride of medianaerodynamic particle size of less than 5 microns in place of oxybutynin.

Example 3 Preparation of Oxybutynin Xinafoate

Example 1 was repeated, using micronized oxybutynin xinafoate salt ofmaximum aerodynamic particle size of about 10 microns in place ofoxybutynin. The oxybutynin xinafoate salt was prepared by as follows: A250 mL, round-bottom flask was equipped with a magnetic stirrer, athermocouple, and a nitrogen-inlet adapter. Under nitrogen, the flaskwas charged with oxybutynin (20.04 g, 0.056 mol.), xinafoic acid (10.69g. 0.057 mol. 1.02 equiv, and methyl tert-butyl ether (100 mL, 5 vol).The solids dissolved almost immediately at approximately 18° C. Thebatch was warmed to 50° C., and at approximately 21° C., crystallizationstarted. The mixture was maintained at 50° C. for one hour, was cooledto 33° C. in air, and then in an ice bath to 3° C. The mixture wasmaintained at <5° C. for one hour and was filtered, and the filter cakewas washed with methyl tert-butyl ether (100 mL). The wet cake was driedin a vacuum oven at 45° C. for one hour.

After salt synthesis, structure was confirmed by 1H NMR and FT-IR (FIGS.5 and 6). HPLC analysis confirmed >99% potency through quantification ofAUC at 15.1 min (FIG. 7). Crystallinity, compound purity, and meltingpoint were also determined by XRPD and DSC (FIGS. 8 and 9). Both testsindicated a highly crystalline substance (DSC detected no coldcrystallization) with a melting point of 105° C. Water content wasdetermined to be 0.057% by KF titration.

Example 4 Comparative Effects of Bronchodilators

Example 1 was repeated, using micronized oxybutynin base, oxybutyninhydrochloride salt, and oxybutynin xinafoate salt of maximum aerodynamicparticle size of about 10 microns in place of oxybutynin. The level ofbronchodilator activity of oxybutynin was compared to Tiotropium andGlycopyrrolate 18 and 24 hours after administration in anaesthetizedguinea pigs. FIGS. 1 and 2 shows comparative effects of pulmonarydelivery of oxybutynin on anaesthetized guinea pigs.

Example 5 Comparative Effects of Bronchodilators: Oxybutynin Xinofoateand Others

Example 1 was repeated, using micronized oxybutynin xinafoate salt ofmaximum aerodynamic particle size of about 10 microns in place ofoxybutynin. The onset of action and resulting systemic levels ofoxybutynin xinafoate was compared to Tiotropium for the first 6 hoursafter administration in anaesthetized guinea pigs. FIG. 3 compareseffects of pulmonary delivery of oxybutynin to Tiotropium onanaesthetized guinea pigs in the initial 6 hours after administration.Oxybutynin showed similar protection against methacholine induced airwayconstriction as Tiotropium; however, did not have as significant aninfluence on cardiovascular conditions. FIG. 4 shows the resultingpharmacokinetics of pulmonary administration of oxybutynin. Systemiclevels of DEO resulting from pulmonary delivery were below the LOQ ofthe detection method and much lower than clinically relevant levels.

Changes may be made without departing from the spirit and scope of theabove-described invention. For example, the oxybutynin may beco-administered with other compounds or agents for reducing adverse sideeffects or to treat the side effect. For example, cholinergic agonistssuch as described in PCT U.S. Ser. No. 09/034,018 may be co-administeredwith the oxybutynin to reduce the effect of dry mouth.

Conclusion

Delivery of micronized particles of oxybutynin directly to the lungs, asneeded, could be found to provide relief to patients suffering fromrespiratory diseases such as asthma and COPD, and also from urge urinaryincontinence and symptoms of stress urinary incontinence and irritablebowel syndrome.

In a guinea pig model of bronchoconstriction, oxybutynin was found tohave a significantly bronchoprotective effect from 0.25 to 24 hourswithout a prolonged significant effect on arterial pressure and heartrate.

Pulmonary administration of oxybutynin also avoids significant formationof the first-pass primary metabolite DEO and thus significantly reducesadverse side effects which traditionally have been associated withadministration of oxybutynin via oral or transdermal delivery.Additionally, dosage amounts of oxybutynin administered via pulmonarydelivery route are significantly lower than dosage amounts of oxybutyninwhen delivered via oral or transdermal delivery routes. Furthermore,pulmonary delivery of oxybutynin results in prolonged therapeutic levelsin the lungs which would permit once or twice daily dosing compared tooral delivery of oxybutynin which typically is administered three timesdaily.

While the invention has been described in detail herein in accordancewith certain preferred embodiments thereof, many modifications andchanges therein may be affected by those skilled in the art.Accordingly, it is intended that the appended claims cover all suchmodifications and changes as may fall within the spirit and scope of theinvention.

We claim:
 1. A method for treating pulmonary disease comprisingdelivering directly to a patient's lungs a therapeutically effectiveamount of oxybutynin in combination with one or more pharmaceuticallyeffective agents, wherein the oxybutynin is selected from the groupconsisting of a palmitate salt, a pamoic salt, and a resonate salt. 2.The method according to claim 1, wherein oxybutynin is delivered in drypowder form.
 3. The method according to claim 1, whereinpharmaceutically effective agent is delivered in dry powder form.
 4. Themethod of claim 1, wherein the pharmaceutically effective agentscomprise bronchodilators, antiinflammatories, corticosteroids, inhaledcorticosteroid, corticosteroid resistance reversal agents, alveolargrowth agents, proteinase inhibitors, or protease inhibitors.
 5. Themethod of claim 4, wherein the bronchodilators comprise long-acting betaagonists and short-acting beta agonists and derivatives orpharmaceutically acceptable salts thereof.
 6. The method of claim 4,wherein the antiinflammatories comprise inhaled corticosteroids,phosphodiesterase inhibitors or leukotriene receptor antagonists.
 7. Themethod of claim 6, wherein the corticosteroids comprise budesonide,fluticasone, beclomethasone, flunisolide, triamcinolone, ciclesonide,loteprednol, fluorometholone, and derivatives or pharmaceuticallyacceptable salts thereof.
 8. The method of claim 4, wherein thecorticosteroid resistance reversal agent comprises vitamin D, syntheticvitamin D, vitamin D analogs, vitamin D receptor agonists, vitamin Dreceptor partial agonists, calcitriol, antioxidants, iNOS inhibitors,Phosphoinositide-3-kinase-delta inhibitors, p38 MAP kinase inhibitors,JNK inhibitors, MIF inhibitors, low-dose theophylline, p-glycoproteininhibitors, macrolides, calcineurin inhibitors, statins and equivalentsthereof.
 9. The method of claim 4, wherein the alveolar growth agentcomprises vitamin A, All Trans Retinoic Acid (ATRA), retinoic acidreceptor (RAR) agonists and RAR selective alveolar growth agents, RARselective agonists, palovarotene and equivalents thereof.
 10. The methodof claim 5, wherein the long-acting beta agonist comprises formoterol,salmeterol, odalaterol, carmoterol or vilanterol.
 11. The method ofclaim 10, further comprising an inhaled corticosteroid wherein theinhaled corticosteroid comprises budesonide, fluticasone, or mometasone.12. The method of claim 11, further comprising a selective agentselected from a soft steroid class, wherein the soft steroid classcomprises ciclesonide or loteprednol.
 13. The method of claim 10,further comprising a corticosteroid resistance reversal agent, whereinthe corticosteroid resistance reversal agent is selected from the groupconsisting of vitamin D, vitamin D analogs, synthetic vitamin D, vitaminD receptor agonists and antagonists, calcitol and equivalents thereof.14. The method of claim 12, further comprising a corticosteroidresistance reversal agent wherein the corticosteroid resistance reversalagent is selected from the group consisting of vitamin D, vitamin Danalogs, synthetic vitamin D, vitamin D receptor agonists andantagonists, calcitol and equivalents thereof.
 15. The method of claim1, wherein the pharmaceutically effective agents comprise a long-actingbeta agonist comprising formoterol, and an alveolar growth agentselected from the group consisting ATRA, cis-retionoic acid andpalovarotene.
 16. The method of claim 1, wherein the pulmonary diseasecomprises asthma, atelectasis, bronchitis, chronic obstructive pulmonarydisease, emphysema, lung cancer, pneumonia or pulmonary edema.
 17. Themethod of claim 1, wherein the pulmonary disease comprises chronicobstructive pulmonary disease, wherein the pharmaceutically effectiveagents comprise long acting muscarinic antagonists.
 18. The methodaccording to claim 1, wherein oxybutynin and the pharmaceuticallyeffective agent is delivered using a dry powder inhaler (DPI) or ametered dose inhaler (MDI) or liquid nebulizer.
 19. The method accordingto claim 18, wherein the dry powder inhaler includes a piezo vibrator.20. The method according to claim 1, wherein oxybutynin is delivered indry powder form having a mass median aerodynamic particle size selectedfrom the group consisting of 0.5-20 microns, 0.5-15 microns, 0.5-10microns, or 0.5-5 microns.
 21. The method according to claim 1, whereinthe dosage of the therapeutically effective amount of oxybutynin iswithin the range of 0.001 to 20 mg per day, 0.02 to 15 mg per day, or0.05 to 10 mg per day administered as needed.
 22. A method for treatingchronic obstructive pulmonary disease comprising delivering directly toa patient's lungs a therapeutically effective amount of oxybutynin incombination with one or more pharmaceutically effective agents, whereinoxybutynin is selected from the group consisting of a palmitate salt, apamoic salt, and a resonate salt.